ABSTRACT Peripheral nerve injury (PNI) is a common consequence of trauma or surgery, and the extent of functional recovery is often unsatisfactory. Moreover, a particular challenge is the repair of ?major? PNI, defined as injuries where a large segment of a nerve is lost (i.e., >5 cm) or more proximal injuries (e.g., brachial plexus or upper arm) that necessitate extremely long distances for axonal regeneration to distal end targets (e.g., hand). Patients who experience major PNI face the high probability of a significant residual functional deficit, even following state-of-the-art surgical reconstruction. To address this gap in care, Axonova Medical has developed a revolutionary approach using tissue engineered nerve grafts (TENGs). TENGs are living three-dimensional nerve constructs that consist of longitudinally aligned axonal tracts spanning discrete neuronal populations. In rat and pig models of PNI, we have shown that allogeneic TENGs can circumvent the key limitations of current reconstructive strategies, notably the ability to (1) accelerate and direct axon regeneration across the zone of injury, and (2) sustain the regenerative environment of distal nerve structures and receptiveness of target muscles to enable host axons to reinnervate long-distance targets. Notably, in an exciting recent study, we found that TENGs serve as a ?living scaffold? to promote rapid nerve regeneration and functional restoration in an extremely challenging major nerve gap (5 cm) model in pigs. The scope of the current proposal is to translate our preclinical protocols to create TENGs using a starting biomass suitable for eventual clinical testing in humans. Through a partnership with Revivicor, Axonova will pursue a xenogeneic product development strategy to build TENGs using so-called ?humanized? pig neurons. Specifically, neurons used to generate TENGs will be sourced from Revivicor's custom and proprietary GalSafe pigs that are genetically engineered to be non-immunogenic when transplanted into humans. These GalSafe TENGs will then be tested in an established xenogeneic PNI repair model using athymic ?nude? rats, and the regenerative efficacy will be compared to benchmarks established using allogeneic TENGs. Axonova's ultimate product will be a combination product (GalSafe TENGs encased in a biodegradable wrap) that will be regulated under a Biologics License Application. Based on the company's preclinical data, TENGs not only represent a superior option to current reconstructive strategies, but a transformative, off-the-shelf solution for repair of currently untreatable major PNI. Successful execution of the milestones in this SBIR proposal will accelerate Axonova's path to clinical testing in humans. GalSafe TENGs represent an innovative product and potentially transformative strategy for major PNI repair that can greatly improve the quality of life for hundreds of thousands of patients in the U.S alone.